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      Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections

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          Abstract

          <p class="first" id="d9221866e490"> <b>Rationale:</b> Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and <i>G551D-CFTR</i> mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. </p><p id="d9221866e498"> <b>Objectives:</b> To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. </p><p id="d9221866e503"> <b>Methods:</b> We studied 12 subjects with <i>G551D-CFTR</i> mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. </p><p id="d9221866e511"> <b>Measurements and Main Results:</b> Ivacaftor produced rapid decreases in sputum <i>Pseudomonas aeruginosa</i> density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting <i>P. aeruginosa</i> strain, and after the first year <i>P. aeruginosa</i> densities rebounded. Sputum total bacterial concentrations also decreased, but less than <i>P. aeruginosa</i>. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. </p><p id="d9221866e528"> <b>Conclusions:</b> Ivacaftor caused marked reductions in sputum <i>P. aeruginosa</i> density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with <i>G551D-CFTR</i> mutations. However, <i>P. aeruginosa</i> airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments. </p>

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          Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs.

          Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.
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            Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection.

            The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF.
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              Divergent, coexisting Pseudomonas aeruginosa lineages in chronic cystic fibrosis lung infections.

              Pseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity.
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                Author and article information

                Journal
                American Journal of Respiratory and Critical Care Medicine
                Am J Respir Crit Care Med
                American Thoracic Society
                1073-449X
                1535-4970
                June 15 2017
                June 15 2017
                : 195
                : 12
                : 1617-1628
                Article
                10.1164/rccm.201609-1954OC
                5476912
                28222269
                e83f57be-e378-4f55-a4c3-811a0617e5a0
                © 2017
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